Project Summary Glioblastoma multiforme (GBM) is the most common form of malignant brain cancer, and is highly aggressive, recurrent, and difficult to treat. The highly infiltrative nature of GBM cells diminishes the clinical efficacy of surgery, and while the prospect of more effective patient-tailored therapies has been explored, such strategies have thus far failed because tumors are invariably highly resistant. Wnt/Planar Cell Polarity (PCP) is a non- canonical Wnt signaling pathway that promotes global directional cues to produce locally polarized cell behavior, leading to increased cell motility, survival and proliferation. Wnt/PCP is critical for embryonic developmental processes, where it modulates cell adhesion and migration. The emerging role for Wnt/PCP signaling in tumor malignancy solidifies the recurring theme that tumors reactivate developmental programs to promote their aggressive behaviors. Expression patterns of Wnt/PCP pathway components strongly suggest that GBM tumors engage the pathway to promote invasiveness and therapeutic resistance, underscoring the notion that a deeper understanding of Wnt/PCP in GBM could uncover novel therapeutic approaches. The hypothesis driving the proposed studies is that Wnt/PCP signaling directly contributes to the malignant properties of GBM, including proliferation, motility, invasiveness and therapeutic resistance. Specific Aim 1 will rigorously characterize the mechanisms by which Wnt/PCP signaling drives the malignant properties of GBM using cellular, molecular and biochemical techniques, focusing on the involvement of the Wnt5a/Fzd7 ligand/receptor pair. Specific Aim 2 will employ knockdown and exogenous expression methods to determine the extent to which PCP components contribute to GBM resistance to targeted therapeutics. Recapitulation of in vitro findings in vivo will be examined in Specific Aim 3 using orthotopic and patient-derived xenograft mouse models of GBM. The successful completion of the project will solidify the involvement of the Wnt/PCP pathway in GBM malignancy, and reveal novel targets for therapeutic intervention into the disease.